OPEN ORIGINAL ARTICLE

Tamoxifen is the standard-of-care treatment for estrogen receptor-positive premenopausal breast cancer. We examined tamoxifen metabolism via blood metabolite concentrations and germline variations of CYP3A5, CYP2C9, CYP2C19 and CYP2D6 in 587 premenopausal patients (Asians, Middle Eastern Arabs, Caucasian-UK; median age 39 years) and clinical outcome in 306 patients. N-desmethyltamoxifen (DM-Tam)/(Z)-endoxifen and CYP2D6 phenotype significantly correlated across ethnicities (R2: 53%, Po10 77). CYP2C19 and CYP2C9 correlated with norendoxifen and (Z)-4-hydroxytamoxifen concentrations, respectively (Po0.001). DM-Tam was influenced by body mass index (Po0.001). Improved distant relapse-free survival (DRFS) was associated with decreasing DM-Tam/(Z)-endoxifen (P 0.036) and increasing CYP2D6 activity score (hazard ratio (HR) 0.62; 95 % confidence interval (CI), 0.43–0.91; P 0.013). Low (o14 nM) compared with high (435 nM) endoxifen concentrations were associated with shorter DRFS (univariate P 0.03; multivariate HR 1.94; 95 % CI, 1.04–4.14; P 0.064). Our data indicate that endoxifen formation in premenopausal women depends on CYP2D6 irrespective of ethnicity. Low endoxifen concentration/formation and decreased CYP2D6 activity predict shorter DRFS